| 18160487 |
Ramnath RD, Sun J, Adhikari S, Zhi L, Bhatia M: Role of PKC-delta on substance P-induced chemokine synthesis in pancreatic acinar cells. Am J Physiol Cell Physiol. 2008 Mar;294(3):C683-92. Epub 2007 Dec 26.
Interaction of the neuropeptide substance P (SP) with its high-affinity neurokinin-1 receptor (NK1R) plays an important role in the pathophysiology of acute pancreatitis. SP is known to stimulate the production of chemokines monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1 alpha, and MIP-2 in pancreatic acinar cells via the activation of NF-kappaB. However, the signaling mechanisms by which the SP-NK1R interaction induces NF-kappaB activation and chemokine production remain unclear. To that end, in the present study, we investigated the participation of PKC in SP-induced chemokine production in pancreatic acinar cells. In this study, we showed that SP stimulated an early phosphorylation of PKC isoform PKC-delta followed by increased activation of MAPKKK MEKK1 and MAPK ERK and JNK as well as transcription factor NF-kappaB and activator protein-1 driven chemokine production. Depletion of PKC-delta with its inhibitor rottlerin or the specific PKC-delta translocation inhibitor peptide dose dependently decreased SP-induced PKC-delta, MEKK1, ERK, JNK, NF-kappaB, and AP-1 activation. Moreover, rottlerin as well as PKC-delta translocation inhibitor inhibited SP-induced chemokine production in a concentration-dependent manner. We also demonstrated that PKC-delta activation was attenuated by CP96345, a selective NK1R antagonist, thus showing that PKC-delta activation was indeed mediated by SP in pancreatic acinar cells. These results show that PKC-delta is an important proinflammatory signal transducer for SP-NK1R-induced chemokine production in pancreatic acinar cells. |
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